The present invention relates to novel xcex2-carboline derivatives, useful as phosphodiesterase inhibitors. The invention further relates to synthesis of the xcex2-carboline derivatives and intermediates used in their preparation. The present invention additionally relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.
Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficiently rigid for satisfactory sexual intercourse. Currently it is estimated that approximately 7-8% of the male population suffers from some degree of ED, the equivalent of at least 20 million men in the United States alone. Since the likelihood of ED increases with age, it is projected that the incidence of this condition will rise in the future as the average age of the population increases.
Male erectile dysfunction may be the consequence of psychogenic and/or organic factors. Although ED is multi-factorial, certain sub-groups within the male population are more likely to present with the symptoms of the disorder. In particular, patients with diabetes, hypertension, heart disease, and multiple sclerosis have a particularly high prevalence of ED. In addition, patients who take certain classes of drugs such as antihypertensives, antidepressants, sedatives, and anxiolytics are more prone to suffer from ED.
Treatments for ED include a variety of pharmacologic agents, vacuum devices, and penile prostheses. Among the pharmacologic agents, papaverine, phentolamine, and alprostadil are currently used in practice. These agents are only effective after direct intracavernosal or intraurethral injection, and are associated with side effects such as priapism, fibrosis, penile pain and hematoma at the injection site. Vacuum devices are a noninasive alternative treatment for ED. These devices produce an erection by creating a negative pressure around the shaft of the penis resulting in an increased blood flow into the corpus cavernosum via passive arterial dilation. Although this form of therapy is frequently successful in ED of organic origin, complaints include the lack of spontaneity and the time involved in using a mechanical device, and difficulty and discomfort with ejaculation. A variety of semi-rigid or inflatable penile prostheses have been used with some success, particularly in diabetic men. These devices are generally considered when other treatment options have failed, and are associated with an increased risk of infection and ischemia.
Recently, the phosphodiesterase V (PDEV) inhibitor, sildenafil (Viagra(copyright)) was approved by the FDA as an orally effective medication for the treatment of ED. Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one and a number of related analogs and their use as antianginal agents are described in U.S. Pat. Nos. 5,250,534 and 5,346,901. The use of sildenafil and related analogs for treating male erectile dysfunction is described in PCT International Application Publication No. WO 94/28902, published Dec. 22, 1994. In clinical studies, the drug improved sexual function in about 70% of the men who suffer from ED of psychogenic or organic etiology. However, the drug showed less dramatic efficacy in patients who had undergone a radical prostatectomy, with improved erections in 43% of patients who took sildenafil versus 15% on placebo. In addition, the use of sildenafil is associated with several undesirable side effects including headache, flushing and disrupted color vision which result from non-selective effects on a variety of tissues. In spite of these shortcomings, the drug is viewed by patients as preferable to other treatments which involve the introduction of medication directly into the penis via injection, the use of an external device or a surgical procedure.
Daugan et.al, in U.S. Pat. No. 5,859,009 (EP 0740668 B1 and WO9519978) describe the synthesis of tetracyclic derivatives as inhibitors of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate specifically phosphodiesterase, and their use in treating cardiovascular disorders. Daugan et.al., in WO97/03675 teach the use of tetracyclic derivatives for the treatment of impotence.
Bombrun et al., in WO 97/43287 describe a series of carboline derivatives, more specifically 2-(substituted alkyl carbonyl) substituted carboline derivatives and their use in treating cardiovascular disorders as inhibitors of cyclic guanosine 3,5-monophosphate, specifically phosphodiesterase.
Ellis et. al., in WO 94/28902 and EP0702555 B1 describes a series of pyrazolpyrimidinone derivatives and their use in treating erectile dysfunction. Campbell, S. F. in WO96/16657 teaches the use of bicyclic heterocyclic compounds for the treatment of impotence (pyrazolopyrimidones); while Campbell et al, in WO,96/16644 teach the use of selective cGMP PDE inhibitors for the treatment of erectile dysfunction.
Ohashi et al., in WO9745427 disclose tetracyclic pyridocarbazole derivatives having cGMP PDE inhibitory effects.
Fourtillan et. al., in WO 96/08490 A1 describe a series of carboline derivatives and their use in the treatment of diseases associated with melatonin activity disorders. Ueki et. al., in U.S. Pat. No. 5,126,448 describe pyridine and 1,2,3,4-tetrahydropyridine derivatives useful as psychotropic drugs having antianxiety effects. Atkinson et. al., in U.S. Pat. No. 3,328,412 describe 1-aryl- and 1-heteroaryl-2-acly-1,2,3,4-tetrahydro-xcex2-carboline derivatives having long lasting analgesic properties.
Sexually stimulated penile erection results from a complex interplay of physiological processes involving the central nervous system, the peripheral nervous system, and the smooth muscle. Specifically, release of nitric oxide from the non-adrenergic, non-cholinergic nerves and endothelium activates guanylyl cyclase and increases intracellular cGMP levels within the corpus cavernosum. The increase in intracellular cGMP reduces intracellular calcium levels, resulting in trabecular smooth muscle relaxation, which, in turn, results in corporal volume expansion and compression of the sub-tunical venules leading to penile erection.
PDEV has been found in human platelets and vascular smooth muscle, suggesting a role for this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissue. In fact, inhibitors of PDEV have been shown to produce endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide. Moreover, PDEV inhibitors selectively lower the pulmonary arterial pressure in animal models of congestive heart failure and pulmonary hypertension. Hence in addition to their utility in ED, PDEV inhibitors would likely be of therapeutic benefit in conditions like heart failure, pulmonary hypertension, and angina.
Agents that increase the concentration of cGMP in penile tissue, either through enhanced release or reduced breakdown of cGMP, are expected to be effective treatments for ED. The intracellular levels of cGMP are regulated by the enzymes involved in its formation and degradation, namely the guanylate cyclases and the cyclic nucleotide phosphodiesterases (PDEs). To date, at least nine families of mammalian PDEs have been described, five of which are capable of hydrolyzing the active, cGMP, to the inactive, GMP, under physiological conditions (PDEs I, II, V, VI, and IX). PDE V is the predominant isoform in human corpus cavernosum. Inhibitors of PDEV, therefore, would be expected to increase the concentration of cGMP in the corpus cavernosum and enhance the duration and frequency of penile erection.
Additionally, selective PDE inhibitors are known to be useful in the treatment of various disorders and conditions including male erectile dysfunction (ED), female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
Accordingly, it is an object of the invention to identify compounds which increase the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV. It is another object of the invention to identify compounds which are useful for the treatment of sexual dysfunction, particularly erectile dysfunction and/or impotence in male animals and sexual dysfunction in female animals. Still another object of the invention is to identify methods for treating sexual dysfunction, especially erectile dysfunction, using the compounds of the present invention.
It is another object of the invention to identify compounds which are useful for the treatment of conditions of disorders mediated by PDEV, such as male erectile dysfunction, female sexual dysfunction, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication or diabetic complications.
We now describe a series of xcex2-carboline derivatives with the ability to inhibit phosphodiesterase type V in enzyme assays and increase the concentration of cGMP in cavernosal tissue in vitro.
The present invention provides novel xcex2-carboline derivative compounds useful as phosphodiesterase inhibitors. More particularly, the present invention is directed to compounds of the general formula (I): 
wherein
R1 is independently selected from the group consisting of halogen, nitro, hydroxy, C1-C8alkyl, C1-C8alkoxy, xe2x80x94NH2, xe2x80x94NHRA, xe2x80x94N(RA)2, xe2x80x94Oxe2x80x94RA, xe2x80x94C(O)NH2, xe2x80x94C(O)NHRA, xe2x80x94C(O)N(RA)2, xe2x80x94NC(O)xe2x80x94RA, xe2x80x94SO2NHRA, xe2x80x94SO2N(RA)2, phenyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
where each RA is independently is independently selected from the group consisting of C1-C8alkyl, aryl (optionally substituted with 1 to 3 RB), C1-C8aralkyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
where each RB is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxyC1-C8alkyl, C1-C8alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)aminoC1-C8alkoxy, di(C1-C8alkyl)aminoacetylC1-C8alkyl, di(C1-C8alkyl)aminoacetylamino, carboxyC1-C8alkylcarbonylamino, hydroxyC1-C8alkylamino, NHRA N(RA)2 and heterocycloalkylC1-C8alkoxy;
n is an integer from 0 to 4;
X is selected from the group consisting of O, S and NRD;
where RD is selected from the group consisting of hydrogen, hydroxy, xe2x80x94ORA, C1-C8alkyl (wherein the alkyl is optionally substituted with one to three substituent independently selected from halogen, carboxy, amino, C1-C8alkylamino, di(C1-C8alkyl)amino, C1-C8alkoxycarbonyl, heteroaryl or heterocycloalkyl), heteroaryl and heteroarylcarbonyl (wherein the heteroaryl may be optionally substituted with phenyl or substituted phenyl, where the phenyl substituents are one to three RB);
R2 is selected from the group consisting of C5-C10alkyl (optionally substituted with 1 to 3 RC), aryl (optionally substituted with 1 to 3 RB), heteroaryl (optionally substituted with 1 to 3 RB) and heterocycloalkyl (optionally substituted with 1 to 3 RB);
where each RC is independently selected from the group consisting of halogen, hydroxy, nitro, NH2, NHRA and N(RA)2;
Z is selected from the group consisting of CH2, CHOH and C(O); provided that when Z is CHOH or C(O), then X is NH;
R4 is selected from the group consisting of hydrogen, hydroxy, carboxy, C1-C6alkylcarbonyl, C1-C6alkoxylcarbonyl, di(C1-C8alkyl)aminoalkoxycarbonyl, di(C1-C8alkyl)aminoC1-C8alkylaminocarbonyl, and xe2x80x94CORF;
where RF is selected from the group consisting of C1-C8alkyl, NH2, NHRA, NRA2, xe2x80x94C1-C8alkylxe2x80x94NH2, xe2x80x94C1-C8alkyl-NHRA, xe2x80x94C1-C8alkyl-NRA2 and xe2x80x94NHxe2x80x94C1-C8alkyl-NRA2;
a is an integer from 0 to 1;
Y is selected from the group consisting of CH2, C(O), C(O)O, C(O)xe2x80x94NH and SO2; 
xe2x80x83is selected from the group consisting of naphthyl, heteroaryl and heterocycloalkyl;
m is an integer from 0 to 2;
R3 is independently selected from the group consisting of halogen, nitro, C1-C8alkyl, C1-C8alkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted with 1 to 3 RB), phenyisulfonyl, naphthyl, C1-C8aralkyl, heteroaryl (optionally substituted with 1 to 3 RB), NH2, NHRA and N(RA)2;
provided that when 
xe2x80x83is 2-furyl or 2-thienyl, then m is an integer from 1 to 2;
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating sexual dysfunction, for example, male erectile dysfunction, impotence, female sexual dysfunction, for example female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor and/or dysmenorrhea in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is a method for increasing the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV, in a male subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
Further exemplifying the invention is a method of producing endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide in a subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
Further illustrating the invention is a method of treating a condition selected from the group consisting of male erectile dysfunction (ED), impotence, female sexual dysfunction, female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is the use of any of the compounds described above in the preparation of a medicament for: (a) treating sexual dysfunction, especially male erectile dysfunction, (b) treating impotence, (c) increasing the concentration of cGMP in penile tissue through inhibition of phosphodiesterase, especially PDEV and/or (d) treating a condition selected from the group consisting of premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof.
The present invention provides novel xcex2-carboline derivatives useful for the treatment of sexual dysfunction, particularly male erectile dysfunction (ED). Although the compounds of the present invention are useful primarily for the treatment of male sexual dysfunction or erectile dysfunction, they may also be useful for the treatment of female sexual dysfunction, for example female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissue of the vagina and clitoris, and of premature labor and dysmenorrhea.
More particularly, the compounds of the present invention are of the formula (I): 
wherein all variables are as defined above.
Preferably, n is 0. Preferably, m is an integer from 0 to 1.
In an embodiment of the present invention X is selected from S or NRD, wherein RD is selected from the group consisting of hydrogen, haloC1-C6alkyl, di(C1-C4alkyl)aminoC1-C6alkyl, heteroaryl, heteroarylC1-C4alkyl, heterocycloalkyC1-C4alkyl, carboxyC1-C4alkyl, C1-C4alkoxycarbonylC1-C4alkyl and heteroarylcarbonyl; wherein the heteroaryl is further optionally substituted with phenyl or substituted phenyl, wherein the substituents on the phenyl are one to two independently selected from RB; and wherein each RB is independently selected from the group consisting of halogen, nitro, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, trifluoromethoxy, amino and di(C1-C4alkyl)amino. Preferably, X is selected from S or NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, di(methyl)amino-n-propyl, di(ethyl)aminoethyl, di(ethyl)amino-n-butyl, N-pyrrolidinylethyl, N-morpholinylethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5-(4-methylphenyl)-2-pyrimidinyl, carboxymethyl, carboxyethyl, 4-chloro-n-butyl, 2-(5-(3-trifluoromethylphenyl)furyl)carbonyl, 2-(5-(3-nitrophenyl)furyl)carbonyl, methoxycarbonylmethyl, methoxycarbonylethyl and 2-benzoxazolyl. More preferably, X is NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinylethyl, carboxyethyl, carboxymethyl, di(ethyl)aminoethyl, N-pyrrolidinylethyl and 5-(4-methylphenyl)-2-pyrimidinyl. Most preferably, X is NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, N-morpholinylethyl, carboxymethyl and N-pyrrolidinylethyl;
Preferably, Z is selected from the group consisting of CH2 and C(O); provided that when Z is C(O), then X is NH.
Preferably, Y is selected from the group consisting of C(O), SO2 and CH2. More preferably, Y is selected from the group consisting of C(O) and CH2. Most preferably, Y is C(O).
In an embodiment of the present invention 
is selected from the group consisting of naphthyl and heteroaryl. Preferably, 
is selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furyl, 3-furyl, 2-benzofuryl, 2-theinyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-(1,2,5-triazolyl), 4-isoxazolyl, 2-pyridyl and 3-pyridyl. More preferably, 
is selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thiazolyl and 2-pyridyl. Most preferably, 
is selected from the group consisting of 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl.
In an embodiment of the present invention, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-(difluoro)methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, pyridyl, phenyl and substituted phenyl; wherein the phenyl substituents are one to two substituents independently selected from halogen, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, cyano, nitro, C1-C4alkoxycarbonyl, di(C1-C4alkyl)amino or di(C1-C4alkyl)aminoC1-C4alkoxy. Preferably, R2 is selected from the group consisting of phenyl, 3,4-methylenedioxyphenyl, 3,4-(difluoro)methylenendioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl, 3,4-dimethoxyphenyl, 4-(dimethylamino)phenyl and 4-(N-(3-dimethylamino)-n-propoxy)phenyl. More preferably, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo-[1,4]-dioxin-6-yl. Most preferably, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl and 2,3-dihydrobenzofuryl.
Preferably, R4 is selected from the group consisting of hydrogen, carboxy, C1-C4alkoxycarbonyl, di(C1-C4alkyl)aminoC1-C4alkoxycarbonyl and di(C1-C4alkyl)aminoC1-C4alkylaminocarbonyl. More preferably, R4 is selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxycarbonyl, dimethylaminoethylaminocarbonyl and methoxycarbonyl. Most preferably, R4 is hydrogen.
In an embodiment of the present invention, R3 is independently selected from the group consisting of halogen, nitro, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, C1-C4aralkyl, pyrazinyl, pyridyl, halogen substituted pyridyl, dimethyl substituted imidazolyl, phenyl, phenyisulfonyl and substituted phenyl; wherein the substituents on the phenyl are one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetylamino, C1-C4alkylsulfonyl, carboxyC1-C4alkylcarbonylamino, hydroxyC1-C4alkylamino, di(C1-C4alkyl)aminoC1-C4alkoxy, di(C1-C4alkyl)aminoacetylamino or heterocycloalkylC1-C4alkoxy. Preferably, R3 is independently selected from the group consisting of chloro, bromo, methyl, n-propyl, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, benzyl, phenylsulfonyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 4-(3-carboxy-n-propyl)carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4-(4-hydroxy-n-butyl)aminophenyl, 2-(dimethylamino)acetylaminop the group consisting of bromo, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 4-(3-carboxy-n-propyl)carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4-hydroxy-n-butyl)aminophenyl, 2-2-(dimethylamino)acetylaminophenyl, 4-pyrazinyl 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl. Most preferably, R3 is selected from the group consisting of t-butyl, methoxy, nitro, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-methylsulfonylphenyl, 2-(dimethylamino)acetylaminophenyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
As used herein, unless otherwise noted, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
The term xe2x80x9calkylxe2x80x9d, whether used alone or as part of a substituent group, shall mean straight or branched chain alkanes of one to ten carbon atoms, or any number within this range. For example, alkyl radicals include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl.
The term xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl group. For example, alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9carylxe2x80x9d indicates an aromatic groups such as phenyl, naphthyl, and the like.
The term xe2x80x9caralkylxe2x80x9d denotes an alkyl group substituted with an aryl group. For example, benzyl, phenylethyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a stable five or six membered monocyclic aromatic ring system containing one to three heteroatoms independently selected from N, O or S; and any nine or ten membered bicyclic aromatic ring system containing carbon atoms and one to four heteroatoms independently selected from N, O or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl or isoquinolinyl. Particularly preferred heteroaryl groups include pyridyl, pyrazolyl, furyl, thiazolyl, thienyl, imidazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, triazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl and benzoxazolyl.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein represents a stable three to eight membered monocyclic ring structure consisting of saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d represents a stable saturated or partially unsaturated, three to eight membered monocyclic ring structure containing carbon atoms and one to four, preferably one to two, heteroatoms independently selected from N, O or S; and any stable saturated, partially unsaturated or partially aromatic, nine to ten membered bicyclic ring system containing carbon atoms and one to four heteroatoms independently selected from N, O or S. The heterocycloalkyl may be attached at any carbon atom or heteroatom which results in the creation of a stable structure. Suitable examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, dithianyl, trithianyl, dioxolanyl, dioxanyl, thiomorpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, 2,3-dihydro-furo[2,3-b]pyridyl, 1,2-(methylenedioxy)cyclohexane, and the like. Particularly preferred heterocycloalkyl groups include pyrrolidinyl, morpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo-[1,4]-dioxin-6-yl.
As used herein, the notation xe2x80x9c*xe2x80x9d shall denote the presence of a stereogenic center.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenylC1-C6 alkylaminocarbonylC1-C6alkylxe2x80x9d substituent refers to a group of the formula 
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. It is further intended that when n or m is  greater than 1, the corresponding R1 or R3 substituents may be the same or different.
The term xe2x80x9csexual dysfunctionxe2x80x9d as used herein, includes male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual arousal dysfunction and female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Abbreviations used in the specification, particularly the Reactions and Examples, are as follows:
Compounds of formula (I) may be prepared according to the processes outlined in more detail below.
Compounds of formula (I) wherein (Y)a is C(O) may be prepared according to a process as outlined in Scheme 1. 
More particularly, a compound of formula (II), wherein X is O, S or NH, a known compound or compound produced by known methods, is reacted with a suitably substituted aldehyde of formula (III), in an organic solvent such as DCM, THF, toluene, and the like, in the presence of an acid catalyst such as TFA, tosic acid, and the like, to produce the corresponding tricyclic compound of formula (IV).
The compound of formula (IV) is reacted with a suitably substituted compound of formula (V), wherein A is halogen, in the presence of a base such as triethylamine (TEA), diisopropylethylamine (DIPEA), sodium carbonate and the like, in an organic solvent such as dichloromethane (DCM), N,Nxe2x80x2-dimethylformamide (DMF), tetrahydrofuran (THF), and the like; or with a suitably substituted compound of formula (V), wherein A is hydroxy, in the presence of a coupling agent such as DCC, DIC, PyBop, PyBrop, and the like, in an organic solvent such as dichloromethane (DCM), N,Nxe2x80x2-dimethylformamide (DMF), tetrahydrofuran (THF), and the like; to produce the corresponding compound of formula (Ia).
Alternatively, compounds of formula (I), wherein X is O, S, or NH and (Y)a is C(O) may be prepared according to a process as outlined in Scheme 2. 
More particularly, a compound of formula (II), wherein X is O, S or NH, is reacted with a suitably substituted compound of formula (VI), wherein A is halogen or hydroxy, in an organic solvent such as DCM, THF, DMF, and the like, to produce the corresponding compound of formula (VII).
The compound of formula (VII) is cyclized by treatment with POCl3, in an organic solvent such as toluene, benzene, and the like, followed by reduction with NaBH4, in an organic solvent such as ethanol, isopropanol, and the like, to produce the corresponding compound of formula (IV).
The compound of formula (IV) is then reacted with a suitably substituted compound of formula (V) to produce the compound of formula (Ia) as outlined in Scheme 1.
Compounds of formula (I), wherein X is O, S or NH and (Y)a is SO2 may be prepared according to a process as outlined in Scheme 3. 
Accordingly, a suitably substituted compound of formula (IV) is reacted with a suitably substituted compound of formula (VIII), wherein A is halogen or hydroxy, a known compound or compound prepared by known methods, in an organic solvent such as DCM, chloroform, DMF, THF, and the like, to produce the corresponding compound of formula (Ib).
Compounds of formula (I) wherein X is O, S or NH and (Y)a is CH2 may be prepared according to a process as outlined in Scheme 4. 
Accordingly, a suitably substituted compound of formula (Ia) is treated with a reducing agent such as LAH, diboron, and the like, preferably LAH, in an organic solvent such as methanol, THF, diethyl ether, and the like, preferably at a temperature in the range of about xe2x88x9220 to 40xc2x0 C., to produce the corresponding compound of formula (Ic).
Compounds of formula (I) wherein (Y)a is CH2 and X is NH, may alternatively be prepared according to a process as outlined in Scheme 5. 
Accordingly, a compound of formula (IVa) is reacted with a suitably substituted compound of formula (IX), wherein Q is halogen, O-tosylate or O-mesolate, in an organic solvent such as DCM, THF, and the like, to produce the corresponding compound of formula (Id).
Compounds of formula (I), wherein X is O, S or NH and (Y)a is (Y)0 (i.e. wherein a is 0, such that Y is absent), may be prepared according to a process as outlined in Scheme 6. 
More specifically, a compound of formula (IV), a known compound or compound produced by known methods, is reacted with a suitably substituted halide of formula (X), a known compound or compound prepared by known methods, in an organic solvent such as toluene, DMF, 1-methyl-2-pyrrolidinone, and the like, preferably at a temperature in the range of about 80 to 250xc2x0 C., to produce the corresponding compound of formula (Ie).
Compounds of formula (I) wherein X is NRD may be prepared by according to a process as outlined in Scheme 7. 
Accordingly, a compound of formula (If) is reacted with a compound of formula (XI), wherein Z is halogen, hydroxy, O-toylate or O-mesolate and a base such as sodium hydride, potassium t-butoxide, and the like, in a solvent such DMF, 1-methyl-2-pyrrolidinone, and the like, to produce the corresponding compound of formula (Ig).
Compounds of formula (I) wherein Z is CHxe2x80x94OH or C(O) may be prepared according to a process as outlined in Scheme 8. 
More particularly, a compound of formula (If) is treated with an oxidizing agent such as DDQ, chloranil, and the like, in a solvent such as THF, methanol, water, and the like, preferably at a temperature in the range of about xe2x88x9278 to about 30xc2x0 C., to produce a mixture of the corresponding compounds of formula (Ih) and (Ii). Preferably, the compounds of formula (Ih) and (Ii) are separated by known methods, such as recrystallization, column chromatography, and the like.
Compounds of formula (I) wherein 
is 2-thiazolyl, may be prepared according to a process as outlined in Scheme 9. 
Accordingly, a suitably substituted compound of formula (IVa) is reacted with Fmoc-NCS, in an organic solvent such as DCM, DMF, THF, and the like, preferably at room temperature, to produce the corresponding compound of formula (XII).
The compound of (XII) is reacted with 20% piperidine, in an alcohol such as methanol, ethanol, and the like, to produce the corresponding amine of formula (XIII).
The amine of formula (XIII) is reacted with a suitably substituted xcex1-halo methyl ketone of formula (XIV), in the presence of an organic solvent or mixture such as DMF, ethanol:dioxane, and the like, in the presence of a base such as TEA, DIPEA, and the like, preferably at a temperature of about 70xc2x0 C., to produce the corresponding compound of formula (Ij).
Compounds of formula (I) wherein (Y)a is C(O)O, may be prepared according to the process outlined in Scheme 10. 
More particularly, a compound of formula (IV) is reacted with a suitably substituted chloroformate of formula (XV) or an anhydride of formula (XVI) in an organic solvent such as DCM, DMF, THF, and the like, to produce the corresponding compound of formula (Ik).
Compounds of formula (I) wherein (Y)a is C(O)xe2x80x94NH may be prepared according to a process as outlined in Scheme 11. 
Accordingly, a compound of formula (IV) is reacted with a suitably substituted compound of formula (XVII), in an organic solvent such as DCM, DMF, THF, and the like, to produce the corresponding compound of formula (Im).
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The utility of the compounds to treat sexual dysfunction can be determined according to the procedures described in Example 10, 11 and 12 herein.
The present invention therefore provides a method of treating sexual dysfunction in a subject in need thereof, which comprises administering any of the compounds as defined herein in a quantity effective to treat sexual dysfunction. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. The quantity of the compound which is effective for treating sexual dysfunction is between 0.1 mg per kg and 20 mg per kg of subject body weight.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
The method of treating sexual dysfunction, particularly male erectile dysfunction (ED) described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 1 mg and 1000 mg, preferably about 10 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of sexual dysfunction, particularly male erectile dysfunction (ED) is required.
The daily dosage of the products may be varied over a wide range from 1 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
Unless otherwise indicated, 1H NMRs were run on a Bruker AC-300.